T. Unlap et Rs. Jope, DIURNAL-VARIATION IN KAINATE-INDUCED AP-1 ACTIVATION IN RAT-BRAIN - INFLUENCE OF GLUCOCORTICOIDS, Molecular brain research, 28(2), 1995, pp. 193-200
The large diurnal rhythm of circulating glucocorticoid levels was used
to determine if physiological fluctuations of glucocorticoids were ca
pable of modulating kainate-induced immediate early gene (IEG) activat
ion, measured as AP-1 DNA binding activity, in rat brain since adminis
tered dexamethasone previously had been shown to be inhibitory. AP-1 a
ctivity in the cerebral cortex 1.5 h after kainate treatment measured
at 08.00 h (4.9-fold control) was more than twice the stimulation obta
ined at 16.00 h (1.8-fold). These times of day are associated with rep
orted low and high levels of circulating glucocorticoids at 08.00 and
16.00 h, respectively. To test if there was a causal relationship, kai
nate-induced AP-1 activity was measured at both times in adrenalectomi
zed rats. Adrenalectomy abolished the attenuation of the response to k
ainate found in intact rats at 16.00 h, indicating that the diurnal fl
uctuations in circulating glucocorticoids contribute to modulation of
IEG responses to kainate. Neither AP-1 activity in the hippocampus nor
cyclic AMP response element activation in either brain region measure
d after kainate treatment was influenced by the time of day or by adre
nalectomy. Immunoprecipitation of glucocorticoid receptors from cortic
al nuclear extracts co-precipitated c-Jun, indicating that the mechani
sm accounting for the supppression of AP-1 activity by glucocorticoids
may involve direct interactions between activated glucocorticoid rece
ptors and AP-1 constituent proteins. These results extend previous rep
orts that administered glucocorticoids inhibit AP-1 activity by demons
trating that this occurs with endogenous glucocorticoids as a conseque
nce of the circadian rhythm of circulating glucocorticoids and demonst
rate that responses to kainate vary dependent upon the time of day.